NO781392L - MARKAPTOALKYLSYLPHONYL-PROLIN DERIVATIVES AND RELATED COMPOSITIONS - Google Patents

Description

This invention relates to the preparation of new mercaptoalkyl-sulfonyl-proline derivatives and related compounds having the formula

where

R and R 2 are each hydrogen or lower alkyl,

is hydrogen, lower alkanoyl or benzoyl, and

m is 2 or 3.

In formula I, the lower alkyl groups are designated

with R and R 2 , linear or branched aliphatic hydrocarbon groups of up to 7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and the like. The C^-C^ groups, and especially the C^-C2~ groups, are preferred.

The lower alkanoyl groups denoted by R^ are the acyl radicals of the lower fatty acids (up to 7 carbon atoms)

such as acetyl, propionyl, butyryl, isobutyryl and the like. Those having up to 4 carbon atoms are preferred. Acetyl is particularly preferred.

Particularly preferred compounds are those of formula I

where m is 2, R and R 2 are each hydrogen and R 2 is hydrogen or lower alkanoyl, especially hydrogen or acetyl.

The new compounds are prepared according to the invention by the following reaction sequence.

Proline or pipecolic acid, preferably in the form of a lower alkyl ester where the alkyl group can be easily removed, e.g. The t-butyl ester is reacted with a haloalkylsulfonyl halide of the formula

where hal means halogen, preferably chlorine or bromine, in the presence of an organic base such as triethylamine, N,N-dimethylaniline, N-methylmorpholine or the like and in an inert organic solvent such as dichloromethane, ether, tetrahydrofuran, dioxane or the like . This coupling reaction leads to a compound of the formula: Reaction of the compound of formula III with a compound of the formula in the presence of an organic base such as those indicated above, and in an organic solvent; such as ether, tetrahydrofuran, dioxane or the like, leads to a product of the formula

Treatment of the product of formula V with trifluoroacetic acid and anisole, when the alkyl group is t-butyl, removes the ester group and leads to the free acid of formula I, i.e. where R is hydrogen.

Treatment of the product of formula V with sodium or potassium hydroxide in water or a lower alcohol, when the alkyl group is methyl or another lower alkyl group and R^ is lower alkanoyl or benzoyl, removes the ester group and the group R^ and results, after acidification, in the free acid of formula I, i.e. where R and R-^ are hydrogen.

Preferably, the thiol of formula IV is one in which R 1 is

lower alkanoyl or benzoyl, e.g. thiolacetic acid, thiolbenzoic acid or the like, with the result that R^ in the product of formula V is lower alkanoyl or benzoyl. A product of formula I where R^ is hydrogen is obtained by treating the product of formula V, either before or after removal of the ester group,

if desired, with ammonia or concentrated ammonium hydroxide solution.

The proline and pipecolic acid esters are prepared as described in German publication 2 703 828 corresponding to Belgian patent 851361.

The asterisks in formula I indicate asymmetric carbon atoms (the carbon atom bearing R 2 is asymmetric when R 2 is different from hydrogen). The compounds where the proline and pipecolic acid part of the molecule are in L-form are preferred.

Further details will be apparent from the examples. The compounds produced according to the invention are inhibitors of angiotensin-converting enzyme and are useful as hypotensive agents, particularly for the reduction of angiotensin-dependent hypertension. By administering a preparation containing one or a combination of the new angiotensin-converting enzyme inhibitors to a hypertensive mammal, it affects the renin -» angiotensin-I -* angiotensin II - course, and the hypertension is reduced or alleviated.

A single dose or preferably two or more daily doses, administered on the basis of approx. 1 to 1000 mg per kg per day, and especially approx. 10 to 200 mg per kg per day, is suitable for producing a reduction of elevated blood pressure. Model animal experiment described by Engel, Proe. Soc. Exp. Biol. With. 143, 483

(1973), represents a valuable guideline.

Preparations containing the new compounds are preferably administered orally, but can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally. The compound or compounds of formula I can be introduced as active ingredient in tablets, capsules or elixirs for oral administration. Sterile solutions or suspensions can be used for parenteral use.

About. 50 to 1500 mg of a compound or compounds of formula I may be mixed with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc., in the usual unit dosage form as is customary in pharmaceutical practice. The amount of active compound is chosen so as to give a dosage in the specified range.

The following examples shall serve to further illustrate the invention and represent preferred embodiments. All temperatures are in °C.

Example 1

1~[[ 2-(acetylthio)ethyl]sulfonyl]-L-proline

a) 1-(vinylsulfonyl)-L-proline-t-butyl ester

L-proline-t-butyl ester (6.9 g, 0.04 mol) and triethylamine

(14 ml, 0.1 mol) is dissolved in 200 ml of dichloromethane and stirred in an ice bath while 2-chloroethanesulfonyl chloride (8.2 g, 0.05 mol) in 100 ml of dichloromethane is added over 20 minutes. After stirring for 2 hours, the mixture is washed with a 5% potassium bisulphate solution,

saturated sodium bicarbonate solution and saline and then evaporated in vacuo. The semi-solid residue is chromatographed on

350 ml of silica gel using. 1:1 ethyl acetate/hexane as

eluent. The major fraction, containing 1-(vinyl-sulfonyl)-L-proline-t-butyl ester, is crystallized from ether/hexane, m.p. 84-87° (7.1 g, 68%). b) 1-[[ 2-(acetylthio)ethyl]sulfonyl-L-proline-t-butyl ester 1-(vinylsulfonyl)-L-proline-t-butyl ester (5.0 g,

0.0192 mol), triethylamine (2.8 ml, 0.02 mol) and thiolacetic acid (1.43 ml, 0.02 mol) are mixed in 100 ml of ether and allowed to stand overnight. The mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine and then evaporated in vacuo to give a yellow oil. The procedure is repeated using half of the above amounts of triethylamine and thiolacetic acid. Workup as in part a) gives the crude product, 1-[[2-(acetylthio)ethyl]-sulfonyl-L-proline-t-buty1-ester, which is filtered through a short silica gel column and crystallized from ether/hexane, m.p. 46-50 (2.9 g, 45%).

c) 1-[[2-acetylthio)ethyl]sulfonyl]-L-proline

The t-butyl ester from part b) (2.9 g, 0.0086 mol) is dissolved,

in 15 ml anisole and 45 ml trifluoroacetic acid and allowed to stand for 1 hour. The mixture is evaporated in vacuo to a gummy residue which is taken up in ethyl acetate and treated with a large volume of hexane. The liquid on

the top is decanted and the process is repeated. The resulting semi-solid is crystallized from ethyl acetate-hexane, m.p. 63-67°

(1.9 g, 78%). [a] = -59.3, c = 1.07^, dimethylformamide.

Example 2

1-[(2-mercaptoethyl)sulfonyl]-L-proline

1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline (640 mg, 0.0023 mol) is dissolved in 5 ml of water and 5 ml of concentrated ammonia and stirred for 1 hour under nitrogen. The solution is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the extracts are washed with saline, dried (MgSO 4 ) and evaporated to an oily residue which is fed to a 75 ml silica gel column. Elution with 10% acetic acid/benzene gives a major fraction which is crystallized from chloroform/hexane to give 440 mg (81%) of 1-t-(2-mercaptoethyl)sulfonyl]-L-proline, m.p. 99-101°.

[α]D= -6 4.3°, c = 1.1£, dimethylformamide.

Example 3

1-[[ 2-(benzoylthio)ethyl]sulfonyl]-L-proline

By using thiolbenzoic acid instead of thiolacetic acid in the method according to example 1b, and then subjecting the product to the method according to example lc, 1-[[2-(benzoylthio)ethyl]sulfonyl-1-L-proline is obtained.

Example 4

1-[[ 2-(acetylthio)ethyl]sulfonyl]-L-pipecolic acid.

a) 1-(vinylsulfonyl)-L-pipecolic acid

By using L-pipecolic acid t-butyl ester instead

L-proline-t-butyl ester by the method according to example la,

1-(vinylsulphonyl)-L-pipecolic acid t-butyl ester is obtained.

b) 1-[[ 2-(acetylthio)ethyl]sulfonyl]-L-pipecolic acid

By using 1-(vinylsulfonyl)-L-pipecolic acid-^

t-butyl ester instead of 1-(vinylsuifonyl)-L-proline-t-butyl ester in the method according to example 1b and then subjecting the product to the process according to example lc, one obtains 1-[[2-acetylthio)-ethyl]sulfonyl]-L-pipecolic acid -t-butyl ester and 1-[[2-(acetylthio)-ethyl]sulfonyl]-L-pipecolic acid.

Example 5

1-[(2-mercaptoethyl)sulfonyl]-L-pipecolic acid

By using 1-[[2-(acetylthio)ethyl]sulfonyl]-L-pipecolic acid instead of 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the method according to example 2, one obtains 1-[( 2-mercaptoethyl)sulfonyl]-L-pipecolic acid.

Example 6

1-[[ 2-(benzoylthio)ethyl]sulfonyl]-L-pipecolic acid

By using 1-(vinylsulfonyl)-L-pipecolic acid-t-butyl ester instead of 1-(vinylsulfonyl)-L-proline-t-butyl ester in the method according to example. 3, 1-[[2-benzoylthio)-ethyl]sulfonyl]-L-pipecolic acid is obtained.

Example 7

1- [[ 2-( acetylthio)- 1- methylethyl] sulfonyl]- L- proline

a) 1-(2-propenylsulfonyl)-L-proline-t-butyl ester

By using 1-chloro-2-propanesulfonyl chloride instead

2-chloroethanesulfonyl chloride by the method according to example la, 1-(2-propenylsulfonyl)-L-proline-t-butyl ester is obtained.

b) 1-[[ 2-( acetylthio)- 1- methylethyl] sulfonyl]- L- proline

By using 1-[2-propenylsulfonyl]-L-proline-t-butyl ester

instead of 1-(vinylsulfonyl)-L-proline-t-butyl ester in the method according to example 1b, and then subjecting the product to the method according to example lc, one obtains 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L- proline t-butyl ester and 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-proline.

Example 8

1-[(2-mercapto-1-methylethyl)sulfonyl]-L-proline

By using 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-proline instead of 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the method according to example 2, one obtains 1 -[2-mercapto-1-methylethyl)sulfonyl]-L-proline .

Example 9

1-[[ 2-(benzoylthio)-1-methylethyl]sulfonyl]-L-proline

By using 1-(2-propenylsulfonyl)-L-proline-t-butyl ester instead of 1-(vinylsulfonyl)-L-proline-t-butyl ester in the method according to example 3, one obtains 1-[ [2-(benzoylthio)- 1-methylethyl]sulfonyl-1-L-proline.

Example 10

1- [[ 2-( acetylthio)- 1- methylethyl] sulfonyl]- L-pipecolic acid

a) 1-(2-Propenylsulfonyl)-L-pipecolic acid t-butyl ester

By using 1-chloro-2-propanesulfonyl chloride instead

2-chloroethanesulfonyl chloride and L-pipecolic acid t-butyl ester instead of L-proline t-butyl ester in the method according to example la,

1-(2-propenylsulfonyl)-L-pipecolic acid t-butyl ester is obtained.

b) 1-[[ 2-( acetylthio)- 1- methylethyl] sulfonyl]- L-pipecolic acid By using 1-(2-propenylsulfonyl)-L-pipecolic acid-t-butyl ester instead of 1-(vinylsulfonyl)-L- proline-t-butyl ester by the method according to example 1b, and then subjecting the product to the method according to example lc, one obtains l-[[2-^

(acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid t-butyl ester and 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid.

Example 11

1-[(2-mercapto-1-methylethyl)sulfonyl]-L-pipecolic acid

By using 1-[[2-(acetylthio)-1-methylethyl]sulfonyl]-L-pipecolic acid instead of 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the method according to example 2, one obtains 1 -[(2-mercapto-1-methylethyl)sulfonyl]-L-pipecolic acid.

Claims (3)

1. Analogy procedure for the preparation of physiologically active compounds with the formula where R and R2 are each hydrogen or lower alkyl, R1 is hydrogen, lower alkanoyl or benzoyl, and m is 2 or 3, characterized in that a compound with the formula where R and m are as indicated above, is reacted with a compound with the formula where R 2 is as above, and hal is halogen, preferably chlorine or bromine, in the presence of an organic base and in an inert organic solvent, to form a compound of the formula where R, R2 and m are as indicated above, which reacts with a compound with the formula where R^ is as stated above, in the presence of an organic base and in an organic solvent, and optionally, if R in the resulting product is lower alkyl, it is converted to hydrogen, and/or optionally, if R 1 in the resulting product is lower alkanoyl or benzoyl, it is converted to hydrogen. 2. Method as stated in claim 1 for the production of 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline, characterized in that starting materials are used where R means hydrogen or is converted to hydrogen, R2 means hydrogen, R^ means acetyl and m is 2. 3. Process as stated in claim 1 for the production of 1-[(2-mercaptoethyl)sulfonyl]-L-proline, characterized in that starting materials are used where R and R1 mean hydrogen or are converted thereto, R2 means hydrogen and m is 2.